The major long-term objective of this program project grant is to develop mechanistic understanding of the action of Interferons (IFNs), other cytokines, and products exhibiting pathogen associated molecular patterns (PAMPs). Collectively, these molecules and their cognate cellular receptors regulate both intercellular communication and the interface between the organisms and their environment through immunomodulatory, anti-viral, anti-microbial, and anti-tumor actions. An important component of this goal has been the integration of mammalian response to viral infection and double stranded RNA (dsRNA) via Toll like receptors (TLRs) with those invoked by cytokine receptor family members. A central theme of the proposal will be to identify the means through which a relatively limited set of molecular players achieve an impressively broad and complex spectrum of cellular response patterns. This will be achieved by analysis of the novel ways in which these receptors engage both JAK/STAT and non-JAK/STAT components to achieve cell type- and stimulus-specific responses. In addition, novel receptor-independent roles for JAK/STAT members will also be explored: Project 1 will explore novel responses to IFNs that are essential in cooperation with the activation of STATs to induce the full spectrum of response. Project 2 will focus upon the role of the IFN-inducible, dsRNA activated protein kinase (PKR) in mediating responses to cytokines and TLRs. Project 3 will focus upon signaling mechanisms utilized by dsRNA and TLRS in promoting expression of IFN-inducible genes. Project 4 will consider mechanisms involved in IL-4/IL-13- and/or STAT6-dependent and -independent control of chemokine gene expression. These projects, supported by one administrative and two state of the art technology cores, will collectively provide valuable mechanistic insight into cytokine and viral actions controlling gene expression.